Humans are susceptible to infection by a variety of pathogenic bacteria. Such infections pose a significant health risk for the human population in general. The human respiratory tract serves as a major portal for the opportunistic entry of bacterial pathogens into the human body. Once established and having multiplied within the respiratory tract, a bacterial pathogen may have severe localised effects or may further affect other vital bodily functions.
Pathogen entry into the respiratory tract can be reduced by the activity of the ciliary and mucus producing cells lining the respiratory tract. Individuals whose normal biological defence mechanisms have been compromised suffer from greater susceptibility to opportunistic infection by bacterial pathogens.
Typical examples of human diseases contracted due to the entry of bacterial pathogens into the respiratory system are bronchitis and pneumonia. Numerous bacterial species are known to be the causative agents of both of these diseases. For example, Streptococcus pneumoniae is a common causative agent of pneumonia while bronchitis may be caused by numerous species of Streptococcus or Staphylococcus. For each of these disease examples, establishment of the bacterial pathogen within the respiratory system is facilitated when either the normal ciliary or mucus producing functions of the respective cells is inhibited. As well, contraction of either of these diseases often leads to the further reduction in the functional abilities of the ciliary and mucus producing cells.
There is, therefore, a need to provide a prophylactic therapy to reduce the risk of, or for the prevention of, infection of the respiratory system by bacterial pathogens.
A further example of the debilitating and often lethal effects due to infection by a bacterial pathogen is evident in persons suffering from cystic fibrosis. Cystic fibrosis ("CF") is a congenital metabolic disorder which is common among Caucasians, affecting approximately 1 in 2,000 newborns. The mode of inheritance is generally autosomal recessive, suggesting that about 5% of the normal population carries the defective gene. CF manifests itself in abnormal secretions of the exocrine glands. Excessive viscid mucus causes obstruction of passageways including pancreatic and bile ducts, the intestines, and bronchi.
Pseudomonas aeruginosa is the predominant respiratory tract pathogen in patients with cystic fibrosis. Once CF patients acquire a P. aeruginosa infection, the infection is rarely, if ever, eradicated and a progressive pulmonary deterioration is initiated, ultimately leading to death. In one study, chronic colonization established in the first five years of life was associated with a 20% survival to 16 years of age, whereas 95% of the patients who remained uncolonized in the first five years of life survived to 16 years of age. Although the extraordinary predisposition of CF patients to colonization and infection with P. aeruginosa has been recognized for many years, a satisfactory explanation for this phenomenon remains elusive.
Presently, there are currently no prophylactic measures or treatments that have resulted in the complete eradication of P. aeruginosa infections in CF patients.
CF patients with established P. aeruginosa infections have been treated by antimicrobial therapy using antibiotics in several prior art therapeutic protocols. However, the complications that have been observed in antibiotic therapy include the following. First, patients with CF dispose of antimicrobial agents more rapidly than do normal individuals, a phenomenon that mandates therapy with higher doses than those normally recommended. Second, strains of P. aeruginosa dissociate into multiple phenotypic forms and often with different antimicrobial susceptibility patterns. Third, since the infection is chronic and the infecting strains of P. aeruginosa are rarely eradicated, resistance to multiple antimicrobial agents frequently develops. Fourth, therapeutic levels of antimicrobial agents in sputum are difficult to achieve because of poor penetration and inactivation. Fifth, the mucoid exopolysaccharide of mucoid strains appears to present a barrier to penetration of some antibiotics. Finally, allergy to certain antibiotics renders therapy with antibiotics difficult in some patients.
Further, anti-inflammatory agents have been used in the therapy of established P. aeruginosa infections in CF patients, as it has been postulated that host-mediated inflammation may be responsible for a large part of the pulmonary damage in the CF lung. Efforts have been made to dampen the inflammatory response in the CF lung by use of a systemic steroidal anti-inflammatory therapy using prednisone. Unfortunately, prednisone therapy carries substantial risks including growth retardation, glucose intolerance and development of cataracts. Preliminary studies are underway to test use of non-steroidal anti-inflammatory agents.
The manner in which P. aeruginosa establishes infection in CF patients has been studied. It is understood that a defect in CF host defences against infection must exist a priori, otherwise infection with P. aeruginosa, an opportunistic pathogen, would not be possible. Despite extensive investigations, a unifying explanation for the peculiar predisposition of CF patients to infection with P. aeruginosa has not been forthcoming.
A range of subtle immunological abnormalities, both primary and secondary, in patients with CF has been identified and incorporated into a feasible pathophysiological scheme. The first of such abnormalities has been identified as the tendency of P. aeruginosa to adhere to buccal and respiratory epithelial cells in patients with CF.
P. aeruginosa is present in the upper and lower respiratory tracts of most older patients with CF, but it is rarely recovered from healthy individuals. The propensity of P. aeruginosa to colonize respiratory epithelia of patients with CF has been attributed to the pathogen's enhanced adhesion to buccal epithelial cells in patients with CF. It has been determined that fibronectin, a glycoprotein which normally coats buccal epithelial cells and prevents adhesion of Gram-negative bacteria, is depleted from the surface of buccal epithelial cells in patients with CF. This provides a possible explanation of the tendency of P. aeruginosa to colonize the upper respiratory tract of patients with CF.
Colonization appears to be established in the upper respiratory tract where nonmucoid P. aeruginosa adhere to buccal epithelial cells in patients with CF, better than to the same cells in normal individuals. Contamination of the lower airways probably occurs due to spontaneous aspiration of respiratory secretions. Since there is defective mucociliary clearance in patients with CF, such aspirated secretions are not cleared and remain in the lower airways. Once P. aeruginosa reaches the lower airways, phagocytosis and killing by macrophages does not occur and a chronic state of infection is established. In this niche, the bacteria are exposed to a new environment which apparently provides the appropriate stimulus for a switch from the nonmucoid to the mucoid phenotype. These mucoid variants may have a survival advantage over nonmucoid strains by virtue of their resistance to phagocytosis and their adhesion to tracheobronchial mucin. Once chronic infection is established, the bacterial density increases dramatically in concert with a down-regulation of toxin production.
As a result of the considerable difficulty and lack of success in treating patients already infected by P. aeruginosa, there is a need to provide a prophylactic therapy to reduce the risk of, or for the prevention of, P. aeruginosa infection, most importantly in patients with CF. Further, there is a need to provide a therapy to reduce the risk of further such infection during the treatment of a patient who has already been infected.
The present invention provides a method for reducing the risk of or preventing the establishment of infection of the respiratory system by bacterial pathogens by treating individuals with a pharmaceutical composition having as an active ingredient either simple or conjugated polysaccharides. For example, treatment of the buccal or respiratory epithelial cells in a human with either simple or conjugated polysaccharides, administered through a variety of mechanisms, can achieve such a result. Use of the method of the present invention may reduce the risk of colonization of the respiratory tract by a bacterial pathogen. By inhibiting the colonization of the bacterial pathogen, the method of the present invention inhibits the establishment of a diseased state in the individual. As well, the present invention may be used for the treatment of individuals already infected by a bacterial pathogen.
Known references show pharmaceutical compositions comprising polysaccharides or their conjugates, including dextran and dextran sulphate as an active ingredient. Of such references, one has shown that such compositions may be effective in treating against infection of human cells by retroviruses. Ueno et al. ("Ueno"), in U.S. Pat. No. 5,100,879, discloses a method for the disinfection of retroviruses by the application of dextran sulphate in concentrations ranging from 0.01 to 1.0 .mu.g/ml to human T-lymphocytes. The molecular weight of the dextran sulphate may range from 2,000 to 10,000 and have a minimum 5% sulphur content. Treatment of T-cells with dextran alone did not prevent T-cell infection by HTLV-III, a causative agent of AIDS. However, in view of the significant differences between the mechanism of infection of T-cells by retroviruses and infection of the respiratory system by bacterial pathogens, Ueno does not teach or suggest a treatment which would be expected to prevent or reduce the risk of respiratory system infection by bacterial pathogens.
Another reference shows a method of treatment of certain bacterial infections using extremely low concentrations of dextran sulphate. Krivan et al. ("Krivan"), in U.S. Pat. No. 5,089,479, discloses a pharmaceutical composition comprised of either sulphatides, dextran sulphate, sialyloligosaccharides or a mixture thereof, coupled with either a water insoluble or water soluble carrier. The composition is used in a method of removing the mycoplasma pathogen from patients infected with either Mycoplasma hominus or Mycoplasma pneumoniae. Also disclosed is a method for detecting mycoplasma pathogens from the said groups through the use of an enzyme-dextran sulphate conjugate.
The use of dextran sulphate at the concentrations disclosed in the present invention for reducing the risk of bacterial infection of the respiratory system is not taught or suggested by Krivan as the concentrations of dextran sulphate utilized by Krivan are approximately 1000 times lower than those disclosed herein. Further, Krivan teaches that dextran has no effect on the treatment of Mycoplasma infections and therefore teaches away from the invention disclosed presently.
Methods for treating patients having CF are known. For example, Edwards et al. ("Edwards"), in U.S. Pat. No. 4,866,072, discloses a method for the treatment of CF by the direct administration of the active ingredient nedocromil sodium, in an aqueous solution in aerosol or oral format, to a patient's lung. The active ingredient may range in concentration from 0.1% to 2.0% w/w for aqueous solutions and from 0.5% to 5.0% w/w for pressurized aerosols. Edwards does not contemplate a method for treatment of the respiratory system against bacterial infection.